PL192961B1 - Orallyadministered pharmacological compositions containing antinlceric agnts and method of obtaining them - Google Patents

Abstract

Comprises an inert nucleus; an active layer which is soluble or disintegrates rapidly in water, obtained from a single aqueous or hydroalcoholic solution-suspension which includes: an active ingredient of anti-ulcerous activity of formula I, II or III, and at least one excipient; and a gastro-resistant outer coating layer obtained from a solution which includes an enteric coating polymer and at least one excipient. The procedure is carried out by 1) coating of the inert nuclei by spraying of a single aqueous or hydroalcoholic suspension-solution; 2) drying of the active layer formed during the spraying of the previous stage; and 3) coating of the charged nuclei by spraying of a solution which includes an enteric coating polymer with at least one excipient in order to obtain a gastro-resistant outer coating layer. <IMAGE>

Description

Description of the invention

The present invention relates to novel oral pharmaceutical compositions containing anti-ulcer compounds and a method for their preparation.

Recently, numerous methods have been developed for the preparation of microgranular release systems. Therein, the mixture of the active ingredient with the excipients can be subjected to kneading, extruding, spheronizing, coating and the like operations. Each of these tableting techniques requires a different technology, and therefore there are many different tableting devices, such as coating bowls or drums, fluidization devices, spheronizing extruders, and centrifugal devices, among others. It would appear that the result would be the same, but in practice there are considerable differences between the tablets obtained with each of these techniques.

Various types of microgranules have been described for the compositions of certain antiulcer benzimidazoles, such as those described in European patents EP No. 247,983, EP No. 244,380, EP No. 23 7200, EP No. 277 741 and WO publication No. 92/22284. These types of compounds are generally acid-non-resistant, and therefore various methods have been developed to protect them from the acidic environment of the stomach.

WO 96/01624 discloses the direct application of an inner layer to a core containing an acid labile H + K + atapase inhibitor without an inert separating layer. This core does not contain an alkaline compound. Thus, the pellets obtained as described herein also do not contain an alkaline compound. In order to produce such pellets, several different pieces of processing equipment are used in each production step.

In European patents EP 247 983 and EP 244 380 the active ingredient is wet kneaded with an excipient mixture, which makes it possible to obtain an alkaline microenvironment. The mixture is extruded and then spheronized. Spheronized microgranules are coated with one or more layers of water-soluble, alkali, buffer solutions, polymer solutions, and the like, followed by a gastric acid-resistant outer layer.

Since this is a spheronization extrusion process, the overall performance of the process depends on many factors. On the one hand, during the extrusion step, it is important to control the dimensions, such as the cross section and length of the extrudate, to avoid a large dispersion of particle size and shape. Both of these factors then contribute to an irregular coating and even cause pores to form unless an additional amount of coating is applied to ensure complete coating of the microgranules, which, however, in turn, can make it difficult to regulate the release of the active ingredient. On the other hand, the properties of the extrudate, such as cohesiveness, firmness and plasticity, also need to be controlled to ensure that the next spheronization proceeds properly.

These difficulties also include the fact that the necessity to use various equipment, such as kneaders, extruders and spheronizers, means that losses during kneading, extrusion and spheronization may be greater than with other tabletting methods.

European Patents EP 237 200 and EP 277 741, the latter published in Spain as ES Patent No. 2 052 697, give an example of powder spray coating (powder application) using a rotary granulator. Spherical granules are described having a core coated with a dust powder that contains an anti-ulcer benzimidazole compound and low-substituted hydroxypropyl cellulose. Also described is a process for the preparation of said spherical granules, characterized in that the nucleating nuclei are moistened by spraying them with a solution of the agglutinator and a sprayed powder containing the active ingredient and slightly substituted hydroxypropyl cellulose is applied to them.

The coating process using a rotary granulator causes considerable attrition, especially in the initial stage. In addition to the abrasion of particles against the walls of the machine due to air pressure, which is normally the case in any fluidized bed, there is a force exerted by the rotating disc of a rotary granulator. This often causes the granules to break and wear.

These problems not only make it difficult to control the release of the active ingredient, but they greatly affect the production capacity of the granules. For this reason, and in order to reduce these difficulties, European patent EP 277 741 proposes the use of very hard nucleating nuclei as a solution.

For the production of the above-mentioned spherical granules, European Patent No. EP 277 741 describes the use of a rotary centrifugal type granulator, such as a rotary granulator.

CF360 from Freund Co. In this procedure, two layers are applied sequentially, but both

Are perfectly separated. The first is filled with the active ingredient with powder excipients simultaneously with the aqueous binder solution. The second is simply filled with powdered excipients along with the aqueous binder solution. The method of introducing the active layer according to EP No. 277 741 means that this layer is significantly porous and is distributed imperfectly uniformly on the initial surface of the neutral particle.

The obtained spherical granules were dried for 16 h and then passed through a cascade array of sieves in order to select the best size range. Finally, the dry sieved granules were placed in a "Wurster" type fluid bed to apply the enteric coating. In summary, the gastric acid-resistant spherical granules described in European Patent EP 277 741 pass through four different devices.

Other examples of coating tablets by a dry powder application method are disclosed in EP Patent No. 642 797 and WO No. 93 25204. European Patent EP 642 797 describes lansoprazole tablets containing a protective, release liner. Several different devices are used to prepare said tablets in each process step: a centrifugal fluid bed granulator for coating the active compound, a fluid bed coater for enteric coating, and a vacuum device used in the drying steps.

In the patent WO 93 25204, oomeoprazole tablets are prepared having a separating layer on the surface with a neutral reaction in a manner which also involves the use of several different devices.

A "Wurster" type or similar fluidized bed method has been provided according to the present invention. This method overcomes the negative factors that affected the prior methods, and introduces substantial changes from the methods of previous patents to tablets containing benzimidazoles.

The present invention relates to a process for the preparation of an oral pharmaceutical composition consisting of:

a) a neutral nucleus;

b) a soluble active layer or a layer which disintegrates rapidly in water consisting of a single aqueous or hydroalcoholic solution-suspension, which contains:

an anti-ulcer active ingredient of general formula I

where A is

in which:

R and R are the same or different and represent a hydrogen group, an alkyl group, an alkoxy group, or an alkoxyalkoxy group;

R ⁴ is hydrogen, an alkyl group, an alkoxy group which may be optionally fluorinated, an alkoxyalkoxy group, or an alkoxycycloalkyl group;

R ¹ is hydrogen, alkyl group, halogen, cyano group, carboxyl group, carboalkoxy group, carboalkyloxyalkyl group, carbamoyl group, carbamoylalkyl group, carboxyl group,

Hydroxy group, alkoxy group, hydroxyalkyl group, trifluoromethyl group, acyl group, carbamoyloxy group, nitro group, acyloxy group, aryl group, aryloxy group, alkylthio group, or alkylsulfinyl group;

R ^{and 2} is hydrogen, an alkyl group, an acyl group, a carboalkoxy group, a carbamoyl group, an alkylcarbamoyl group, a dialkylcarbamoyl group, an alkylcarbonylmethyl group, an alkoxycarbonylmethyl group, or an alkylsulfonyl group; m is an integer ranging from 0 to 4; or a compound of formula II or III:

and

- an alkaline compound i

- at least one pharmaceutically acceptable excipient selected from the group consisting of: a binder, an alkaline compound, a surfactant, a filler and a disintegrating and swelling excipient; and

(c) an outer skin resistant to the stomach environment made of a solution containing:

- coating polymer i

- at least one excipient selected from the group consisting of: plasticizer, surfactant, pigment and lubricant, characterized by:

1) coating the inert nucleus by spraying an aqueous or hydroalcoholic solution-suspension which contains the active ingredient, an alkaline compound and a pharmaceutically acceptable excipient or excipients;

2) drying the active layer produced during the spraying in the previous step; and

3) coating the nuclei containing the active ingredient by spraying a solution that contains a polymer forming an active coating on the stomach environment and a pharmaceutically acceptable excipient to form an outer coating layer resistant to the environment of the stomach, all steps being carried out in a single bed fluid bed coater.

Preferably, additional drying is carried out after the step of coating the nuclei containing the active ingredient.

The process of the invention uses a pharmaceutically acceptable excipient in an aqueous or hydroalcoholic suspension solution selected from the group of compounds such as sucrose, starch, methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, or dextrin alone or dissolved in a mixture of in water, ethanol or in a mixture containing 50% by volume of both components.

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Preference is given to using an alkaline compound selected from the group consisting of trisodium phosphate, disodium phosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, aluminum hydroxide, aluminum, calcium, sodium or potassium phosphate or citrate, mixed aluminum magnesium compounds Al ₂ O ₃ 6 MgO · CO ₂ · 12 H ₂ O or MgO · Al ₂ O ₃ · 2 SiO ₂ nH ₂ O and alkaline amino acids.

The process of the invention uses a pharmaceutically acceptable excipient present in an aqueous or hydroalcoholic suspension solution containing a surfactant selected from the group consisting of sodium lauric sulfate, polysorbate, poloxamer or other ionic and non-ionic surfactants and containing a filler material selected from the group that it contains lactose, starch, sucrose and microcrystalline cellulose and a disintegrating and swelling agent selected from the group consisting of starch, calcium carboxymethyl cellulose, sodium starch glycolate and L-hydroxypropyl cellulose.

Preferably, a gastric environment-resistant coating polymer present in the gastric environment-resistant outer coating is used selected from the group which comprises methyl cellulose, hydroxyethyl cellulose, hydroxybutyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropylene glycol, polypropylene glycol, cellulose. phthalic, hydroxypropyl methylcellulose phthalates, hydroxymethylcellulose succinate acetate, sodium carboxymethylaminopectin, chitosan, alginic acid, carrageenes, galactomanians, tragacanth, shellac, agar-agar, acrylics, guar gum and poly (methacrylate) quantas and their salts, polyvinyl alcohol, polyethylene propylene oxides and mixtures thereof.

Preferably the process of the invention uses a pharmaceutically acceptable excipient present in the outer coating resistant to the stomach environment, containing a plasticizer selected from the group consisting of triethyl citrate, polyethylene glycol, cetyl alcohol, and stearyl alcohol, and containing a surfactant selected from the group, which comprises sodium lauric sulfate, polysorbate and poloxamer, and comprising a pigment selected from the group which comprises titanium dioxide and iron sesquioxide, and which comprises a lubricant selected from the group which comprises talc, magnesium stearate and glyceryl monostearate.

The subject of the invention is an oral pharmaceutical composition, characterized in that it contains an inert nucleus constituting a neutral spherical microgranule, which contains two or more substances such as: sorbitol, mannitol, sucrose, starch, microcrystalline cellulose, lactose, glucose, trehalose, maltite or fructose. .

The oral pharmaceutical composition according to the invention is obtained by the method according to the invention.

The pharmaceutical composition according to the invention preferably comprises an inert nucleus having an initial size of from 200 to 1800 µm, preferably from 600 to 900 µτι.

The compositions according to the invention solve the difficulties of the prior art in a satisfactory and new way, while at the same time showing resistance to dissolution in the acidic environment of the stomach and dissolving rapidly in an alkaline environment with disintegration of the granules and excellent active ingredient release.

The present invention satisfactorily solves the difficulty of coating a neutral nucleus with an aqueous or hydroalcoholic solution-suspension containing an anti-ulcer compound, which is usually very unstable in an acidic environment, and upon dissolving in an aqueous medium in the presence of disintegrating and swelling excipients, an increase in viscosity occurs which makes spraying very difficult to spray. them on an inert nucleus.

A "Wurster" type fluidized bed or the like in which the coating is performed reduces the attrition caused by rotary granulation. For this reason, particularly hard inert kernels must be used.

The microgranules are not subjected to any kneading or extruding, nor is their inert core coated by spraying the powder together with the aqueous binder. The microgranule used according to the invention consists of an inert nucleus which is coated with a single active layer, which is an aqueous or hydroalcoholic solution-suspension which comprises: an anti-ulcer component and at least one disintegrating and swelling excipient, a binder, an alkalizing medium, a surfactant and a diluent .

When a single solution-suspension is sprayed onto the inert nucleus, a less porous and more homogeneous product is obtained than with the prior art processes, and all subsequent operations are greatly simplified.

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Also, unlike the prior art (EP no. 244 380, EP 277 983, EP 237 200, EP 277 741 and PCT WO / 92/22289), in which the production was carried out using several different devices, the entire method according to the invention was is performed in a single fluidization unit, which reduces time and product wastage and complies with "Good Manufacturing Practice" (GMP). Moreover, by omitting a number of operations and intermediate steps, a significant reduction in the investment in equipment and buildings is achieved.

The inert nuclei used according to the invention are inert spherical microgranules which may contain two or more substances such as sorbitol, mannitol, sucrose, starch, microcrystalline cellulose, lactose, glucose, trehalose, maltite and fructose. Their initial size may be from about 200 to about 1800 µm, preferably from about 600 to about 900 µm.

A single aqueous or hydroalcoholic solution-suspension which is sprayed onto the inert nucleus consists of an antiulcer active ingredient and other excipients. The hydroalcoholic environment consists of water-ethanol mixtures in a ratio of less than 1 to 50% by volume, preferably from 25 to 45% by volume.

The oral pharmaceutical composition according to the invention comprises an anti-ulcer compound as an active ingredient, characterized in that it also comprises:

a) neutral nucleus;

b) a soluble active layer or a layer which disintegrates rapidly in water consisting of a single aqueous or hydroalcoholic solution-suspension, which contains:

an anti-ulcer active ingredient of general formula I

where A is

in which:

R and R are the same or different and represent a hydrogen group, an alkyl group, an alkoxy group, or an alkoxyalkoxy group;

R ⁴ is hydrogen, an alkyl group, an alkoxy group which may be optionally fluorinated, an alkoxyalkoxy group, or an alkoxycycloalkyl group;

R ¹ is hydrogen, alkyl group, halogen, cyano group, carboxyl group, carboalkoxy group, carboalkyloxyalkyl group, carbamoyl group, carbamoylalkyl group, hydroxyl group, alkoxy group, hydroxyalkyl group, trifluoromethyl group, acyl group, carbamoyloxy group, nitro group, nitro group, an acyloxy group, an aryl group, an aryloxy group, an alkylthio group, or an alkylsulfinyl group;

₂

R represents a hydrogen group, an alkyl group, an acyl group, a carboalkoxy group, a carbamoyl group, an alkylcarbamoyl group, a dialkylcarbamoyl group, an alkylcarbonylmethyl group, an alkoxycarbonylmethyl group, or an alkylsulfonyl group; and m is an integer ranging from 0 to 4;

Or a compound of formula II or III:

and

- at least one pharmaceutically acceptable excipient selected from the group consisting of: a binder, an alkaline compound, a surfactant, a filler and a disintegrating and swelling excipient; and

(c) an outer skin resistant to the stomach environment made of a solution containing:

- coating polymer i

- at least one excipient selected from the group consisting of: plasticizer, surfactant, pigment and lubricant.

Excipients present in the solution-suspension of the active compound of formulas I, II or III which are sprayed onto the inert nucleus include:

a) a binder or mixture of binders, such as: sucrose, starch, methylcellulose, carboxymethylcellulose (CMC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), dextrin or gum arabic, dissolved in water, or mixed with ethanol in water (at or below 50% by volume);

(b) an alkaline compound, such as trisodium or disodium phosphate, magnesium oxide, hydroxide or carbonate, aluminum hydroxide, aluminum, calcium, sodium or potassium carbonate, phosphate or citrate, mixed aluminum-magnesium compounds Al ₂ O ₃ 6 MgO CO ₂ · 12 H ₂ O or MgO · Al ₂ O ₃ · 2 SiO ₂ · nH ₂ O or similar alkaline compounds and amino acids;

c) surfactants such as sodium lauric sulfate, polysorbate, poloxamer, and ionic and nonionic surfactants;

d) a filler such as lactose, starch, sucrose or microcrystalline cellulose,

e) a disintegrating and swelling compound such as starch, calcium carboxymethyl cellulose (CMCCa), sodium starch glycolate or low-substituted hydroxypropyl cellulose (L-HPC).

After the microgranules have been formed by spraying an aqueous or hydroalcoholic suspension solution containing the active ingredient, they are dried and coated with a enteric coating layer.

The following polymers can be used as a coating resistant to the stomach environment: methyl cellulose, hydroxyethyl cellulose (HEC), hydroxybutyl cellulose (HBC), HPMC, ethyl cellulose, hydroxymethyl cellulose (HMC), HPC, poly (oxyethylene glycol), cellulose phthalate, cellulose acetate HMC acetate, sodium carboxymethylaminopectin, chitosan, alginic acid, carrageenes, galactomanates, tragacanth, shellac, agar-agar, acacia, guar gum and xanthan gum, poly (acrylic acids), poly (methacrylic acids) and their salts, poly (alcohol) vinyl) (PVA), polyethylene and propylene oxides, and mixtures thereof.

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In addition to the polymer resistant to the stomach environment, plasticizers such as triethyl citrate (TEC), polyethylene glycol (PEG), cetyl alcohol, and stearyl alcohol; surfactants such as sodium lauric sulfate, polysorbate and poloxamer; pigments such as titanium dioxide, iron sexoxide; lubricants such as talc, magnesium stearate or glyceryl monostearate, and mixtures thereof.

Another object of the invention is a process for the preparation of said galenical compositions.

The method of producing oral pharmaceutical compositions according to the invention consists in the following:

1) coating of the inert nucleus by spraying an aqueous or hydroalcoholic solution-suspension which contains:

an anti-ulcer active ingredient of formula I, II or III i

- at least one pharmaceutically acceptable excipient selected from the group consisting of a binder, an alkaline compound, a surfactant, a filler and a disintegrating and swelling excipient;

2) drying the active layer produced during the spraying in the previous step; and

3) coating of nuclei containing the active ingredient by spraying a solution that contains a polymer forming a gastric environment resistant coating with at least one excipient selected from the group consisting of a plasticizer, surfactant, pigment and lubricant to produce an outer coating layer resistant to the gastric environment .

Optionally, additional drying is carried out after step 3) of coating the nuclei containing the active ingredient.

A description of the process of the invention is provided below, with particular reference to the process and amounts used for each ingredient.

In a suitably sized tank, an alkaline, aqueous or hydroalcoholic solution is prepared by introducing an alkaline compound in an amount of 0.1 to 5% by weight of an alkaline compound into an aqueous or hydroalcoholic carrier. The benzimidazole anti-ulcer compound and the other anti-ulcer compound (from 6 to 25% by weight) are introduced with stirring together with the filler (from 3 to 15% by weight). The surfactant (from 0.01 to 3% by weight), the binder and the disintegrant and swelling agent are added to the obtained solution-suspension in amounts of 2 to 10% by weight, respectively, taking into account the application times of the prepared solution.

The mixture is homogenized at room temperature (23 ± 2 ° C) while continuously mixing. Agitation is still applied during the step of spraying the active layer onto the neutral tablets; this method is carried out using a "Wurster" type fluidized bed or similar device into which 850 μm inert nuclei are poured. The following spray conditions: atomization pressure of 2 to 3 bar, product temperature of from 35 to 45 ° C, air volume of 700 to 1200 m ³ / h at a temperature of from 80 to 90 ° C, a nozzle diameter of 1.2 mm.

After the active ingredient introduction step, the nuclei coated with the active ingredient were dried in the same machine. The air flow is maintained between 600 and 800 m ³ / h at a temperature of from 35 to 45 ° C for 45 minutes.

In the next step, a coating that is resistant to the stomach environment is applied to the active tablets in the same device. An aqueous or organic dispersion is prepared containing from 10 to 40% by weight of a polymer resistant to the stomach environment. Thereafter, from 0.2 to 10% by weight of a plasticizer is dissolved in water and, while stirring, up to 3% by weight of surfactant and, if necessary, from 0 to 5% by weight of pigments and 0.5 to 16% by weight, are added. by weight lubricants. After homogenization, from 25 to 45% by weight of the stomach-resistant polymer dispersion is introduced while stirring.

Additional drying can be carried out with an ordinary dryer to reduce the moisture content.

Above 90% by weight of the obtained microgranules should have a diameter ranging from about 0.4 to about 1.95 mm, preferably in the range from about 0.5 to about 1.8 mm.

The kernels of the present invention resist dissolution in an acidic environment, dissolve rapidly in an alkaline environment and are stable over long storage periods, have excellent disintegration properties and the active layer is more homogeneous and less porous than the granules described in previous patents.

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The present invention satisfactorily solves the difficulties of the prior art since a solution-suspension is used to coat inert nuclei.

In this step, a "Wurster" type fluidized bed or the like is used, in which the attrition is significantly less than with the rotary granulator, which must be used when the nucleus of the embryo is coated with an active powder and a binder solution.

From the beginning of the introduction of the active ingredient into the inert nuclei to the end of the gastric resistant coating, the entire process is carried out in a single "Wurster" type fluidized bed or the like, unlike other methods that take place on several different machines.

Figure 1 is a scanning electron microscope photograph showing a cross section of the ansoprazole tablet of Example I.

Figures 2 and 3 are scanning electron microscopy photos showing other details of the layers present.

Figure 4 is a photograph showing the porosity of the coating.

Figures 5, 6 and 7 are cross sectional photos of the omeprazole tablet of Example 2 with a gastric environment resistant coating containing a compound of formula I.

Figure 8 is a photograph showing the uniformity of the coating and several pores in the coating.

Examples

For a better understanding of the above description, some examples are given which generally and in a non-limiting manner represent a practical example of an embodiment of the present invention.

P r z k ł a d I

In a sufficiently volume stainless steel vessel, an alkalizing aqueous trisodium phosphate solution was prepared and charged with lansoprazole, lactose and sodium lauric sulfate while vigorously stirring.

After a homogeneous mixture was obtained, 13.50% by weight of a colloidal aqueous solution of hydroxypropylmethyl cellulose was introduced with continuous mixing to ensure uniformity of the product. Then, L-HPC was introduced into the solution-suspension. Stirring continued until sprayed onto neutral tablets.

Lansoprazole 1.29 kg Sodium lauric sulfate 5.28 · 10 ^-3 kg Crystalline disodium phosphate 0.052 kg Hydroxypropyl methylcellulose 0.8 kg Lactose 0.51 kg Hydroxypropyl cellulose 0.39 kg Water 14.28 kg

10 kg of neutral nuclei containing from 62.5 to 91.5% by weight of sucrose and from 37.7 to 8.5% by weight of starch, with an average diameter of 800 μm, were introduced into a Niro fluidized bed of the "Wurster" type and were coated with the suspension solution previously prepared under the following conditions: air flow of 250 m ³ / h, nozzle diameter 1.2 mm, spray pressure 2.5 bar, the yield of the product spray 100 g / min, air temperature 85 ° C product temperature 38 ° C.

Then dried in the same bed nucleus coated with an active ingredient within 45 minutes with air at 35 ° C with air flow of 250 m ³ / h in order to obtain a suitable humidity.

A gastric environment-resistant coating was applied to the dry granules by spraying the gastric environment-resistant suspension solution below, which had been prepared from an aqueous polyethylene glycol solution into which other excipients were added while stirring.

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Talc 0.57 kg Titanium dioxide 0.18 kg Poly (ethylene glycol) 6000 0.18 kg Polysorbate 0.08 kg Eudragit L30D55 5.78 kg Water 12.14 kg

₃

The operating conditions were as follows: air flow 250 m / h, nozzle diameter 1.2 mm, atomization pressure 2.5 bar, product atomization efficiency 100 g / minute, air temperature 70 ° C, product temperature 36 ° C.

Possible drying the coated tablets were performed for 45 minutes with air at a temperature of 35 TEM ₃ ° C with air flow of 250 m / h.

The results of stability studies performed on a batch of Lansoprazole tablets under different storage conditions are summarized below: at room temperature and 40 ° C and 75% relative humidity. Storage conditions: at room temperature. Container: Topaz glass bottle with a silica gel pouch inside, a metal threaded cap and a flexible seal.

Time of trial Color Stomach environment resistance Freeing- no Ingredient active Moisture- nity Transmittance at 440 nm feeding creamy white 98.8% 82.8% 33.0 mg / 370 mg 1.62% 97% One month creamy white 98.6% 82.0% 33.0 mg / 370 mg 1.50% 97% 3 months creamy white 97.0% 80.9% 32.8 mg / 370 mg 1.48% 97% 6 months creamy white 97.4% 79.8% 32.0 mg / 370 mg 1.47% 96% 18 months creamy white 97.4% 79.8% 31.0 mg / 370 mg 1.46% 95%

Storage conditions: temperature 40 ° C, humidity 75%. Container: topaz glass bottle with a silica gel pouch inside, a metal threaded cap and a flexible seal.

Time of trial Color Stomach environment resistance Freeing- no Ingredient active Moisture- nity Transmittance at 440 nm feeding creamy white 98.8% 82.8% 33.0 mg / 370 mg 1.62% 97% One month creamy white 97.6% 81.2% 32.0 mg / 370 mg 0.90% 95% 3 months creamy white 97.8% 80.8% 31.8 mg / 370 mg 1.27% 93% 6 months creamy white 96.9% 79.8% 31.2 mg / 370 mg 1.32% 92%

There were no significant differences in the values of gastric environmental resistance and active ingredient release compared to the initial values, irrespective of the storage conditions. Both tests were performed according to the Farmacopea USP XXIII.

The active ingredient content was determined by high resolution liquid chromatography. The content of degradation products was estimated on the basis of transmittance measurements at 440 nm.

Based on these results, it can be concluded that there are no big differences from baseline. A slight decrease in activity was found after 6 months of storage at 40 ° C, which may explain the reduction in transmittance at 440 nm.

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The results demonstrate the chemical stability of the active ingredient under the storage conditions tested. Moreover, no significant changes in the moisture content of the tablets were found during storage, indicating the physical stability of the composition.

All the results show the stability of the compositions according to the invention, which furthermore differ from the compositions according to the prior art in that they do not have an intermediate separating layer between the active layer and the gastric environment resistant layer.

Scanning electron microscopy studies were performed using the Jeol JSM6400 scanning microscope. Photo 1 is a cross-section of the lansoprazole tablet of Example 1, clearly showing the presence of a neutral nucleus, an active layer closely bound to the nucleus, and a gastro-resistant coating. Pictures 2 and 3 show further details of both layers more clearly, revealing the absence of an intermediate separating layer between them. Photo 4 shows a low porosity of the coating. The lack of surface pores explains the physicochemical stability of the tablet.

P r z x l a d II

An alkalizing aqueous solution of disodium phosphate was prepared in a stainless steel tank, and omeprazole, lactose and sodium lauric sulfate were introduced into it. Stirring until a homogeneous mixture was obtained, then 12.55% by weight of a colloidal aqueous solution of hydroxypropylmethyl cellulose and low-substituted hydroxypropyl cellulose (L-HPC) was introduced. Stirring continued until sprayed onto neutral tablets.

The qualitative and quantitative composition of the solution-suspension is given below:

Omeprazole 1.38 kg Sodium lauric sulfate 5.28 · 10 ^-3 kg Crystalline disodium phosphate 0.052 kg Hydroxypropyl methylcellulose 0.68 kg Lactose 0.51 kg Hydroxypropyl cellulose 0.39 kg Water 14.28 kg

10 kg of neutral nuclei containing from 62.5 to 91.5% by weight of sucrose and from 37.5 to 8.5% by weight of starch, with an average diameter of 800 μm, were introduced into a Niro fluidized bed of the "Wurster" type and coated with the previously prepared solution - suspension of the following conditions _three hands: the air flow of 250 m / h, nozzle diameter 1.2 mm, spray pressure 2.5 bar, the yield of the product spray 100 g / min, air temperature 75 ° C product temperature 35 ° C.

Then, the nuclei coated with the active ingredient were dried in the same bed for ₃ minutes with air at 35 ° C with an air flow of 250 m / h in order to obtain the appropriate humidity.

A gastric environment-resistant coating was applied to the dry granules by spraying the gastric environment-resistant suspension solution given below, which was prepared from an aqueous polyethylene glycol solution, into which other excipients were added, while stirring continuously (composition I), or from an organic solution containing acetone and ethyl alcohol to which other ingredients of the excipient have been added while stirring continuously (composition II).

Composition I

Talc 0.57 kg Titanium dioxide 0.18 kg Poly (ethylene glycol) 6000 0.18 kg Polysorbate 0.08 kg Eudragit L30D55 5.78 kg Water 12.14 kg

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Composition II

Acetone 20.86 kg Hydroxypropyl methylcellulose phthalate 2.35 kg Diethyl phthalate 0.011 kg Ethanol 8.93 kg

For this purpose worked under the following conditions: air flow of 250 m ³ / h, nozzle diameter 1.2 mm, spray pressure 2.5 bar, the yield of the product spray 100 g / min, air temperature 70 ° C Product temperature 36 ° C.

The coated tablets were dried for 45 minutes with air at 35 ° C with air flow of 250 m ³ / h.

The results of stability tests performed on a batch of Omeprazole tablets in various storage conditions are presented below: at room temperature and at 30 ° C and 65% relative humidity. Storage conditions: at room temperature. Container: Topaz glass bottle with a silica gel pouch inside, a metal threaded cap and a flexible seal.

Time of trial Color Stomach environment resistance Freeing- no Ingredient active Moisture- nity Transmittance at 440 nm feeding creamy white 99.0% 94.0% 20.4 mg / 233 mg 1.12% 98% One month creamy white 99.6% 93.7% 20.5 mg / 233 mg 1.14% 98% 3 months creamy white 98.9% 93.5% 20.6 mg / 233 mg 1.20% 98% 6 months creamy white 98.6% 93.0% 20.3 mg / 233 mg 1.25% 98% 18 months creamy white 97.4% 91.0% 20.2 mg / 233 mg 1.35% 96%

Storage conditions: temperature 30 ° C, humidity 65%. Container: Topaz glass bottle with a silica gel pouch inside, a metal threaded cap and a flexible seal.

Time of trial Color Stomach environment resistance Freeing- no Ingredient active Moisture- nity Transmittance at 440 nm feeding creamy white 99.0% 94.0% 20.4 mg / 233 mg 1.12% 98% One month creamy white 98.0% 93.8% 20.0 mg / 233 mg 1.16% 97% 3 months creamy white 97.8% 93.1% 20.5 mg / 233 mg 1.26% 96% 6 months creamy white 97.0% 92.6% 20.3 mg / 233 mg 1.37% 95%

The values of gastric resistance, humidity and release demonstrate the physical stability of the active ingredient under the storage conditions tested. Moreover, the active ingredient contents and the transmission values at 440 nm indicate the chemical stability of the composition.

All the results show the stability of the compositions according to the invention, which furthermore differ from the compositions according to the prior art in that they do not have an intermediate separating layer between the active layer and the gastric environment resistant layer. Scanning electron microscopy studies were performed using the Jeol JSM6400 scanning microscope. Pictures Nos. 5, 6 and 7 show a cross section of an omeprazole tablet of Example 2 with a gastric environment resistant coating of composition I, clearly showing the presence of a neutral nucleus, an active layer closely related to the nucleus and a gastric environment resistant coating. Photo 8 shows the homogeneity of the coating and the small number of pores, factors that improve the physical stability of the tablet.

Claims (15)

1) coating the inert nucleus by spraying an aqueous or hydroalcoholic solution-suspension which contains the active ingredient, an alkaline compound and a pharmaceutically acceptable excipient or excipients; 1. A method for the manufacture of an oral pharmaceutical composition consisting of: a) a neutral nucleus; b) a soluble active layer or a layer which disintegrates rapidly in water consisting of a single aqueous or hydroalcoholic solution-suspension, which contains: an anti-ulcer active ingredient of general formula I wherein A is wherein: R ³ and R ⁵ are the same or different, and represent a hydrogen group, an alkyl group, an alkoxy group, or an alkoxyalkoxy group; R ⁴ is hydrogen, an alkyl group, an alkoxy group which may be optionally fluorinated, an alkoxyalkoxy group, or an alkoxycycloalkyl group; R ¹ is hydrogen, alkyl group, halogen, cyano group, carboxyl group, carboalkoxy group, carboalkyloxyalkyl group, carbamoyl group, carbamoylalkyl group, hydroxyl group, alkoxy group, hydroxyalkyl group, trifluoromethyl group, acyl group, carbamoyloxy group, nitro group, nitro group, an acyloxy group, an aryl group, an aryloxy group, an alkylthio group, or an alkylsulfinyl group; ₂ R represents a hydrogen group, an alkyl group, an acyl group, a carboalkoxy group, a carbamoyl group, an alkylcarbamoyl group, a dialkylcarbamoyl group, an alkylcarbonylmethyl group, an alkoxycarbonylmethyl group, or an alkylsulfonyl group; and m is an integer ranging from 0 to 4; or a compound of formula II or III: PL 192 961 B1 i - a compound with an alkaline reaction i - at least one pharmaceutically acceptable excipient selected from the group consisting of: a binder, an alkaline compound, a surfactant, a filler and a disintegrating and swelling excipient; and (c) an outer skin resistant to the stomach environment made of a solution containing: - coating polymer i - at least one excipient selected from the group consisting of: plasticizer, surfactant, pigment and lubricant, characterized by: 2. The method according to p. The process of claim 1, characterized in that additional drying is performed after the step of coating the nuclei containing the active ingredient. 2) drying the active layer produced during the spraying in the previous step; and 3. The method according to p. A method as claimed in claim 1, characterized in that a pharmaceutically acceptable excipient in an aqueous or hydroalcoholic suspension solution is used selected from the group of compounds such as sucrose, starch, methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidine, or PVP gum alone, either in a mixture, dissolved in water, ethanol or in a mixture of 50% by volume of both components. 3) coating the nuclei containing the active ingredient by spraying a solution that contains the gastric environment-resistant coating polymer and the pharmaceutically acceptable excipient to form the gastric environment-resistant outer coating layer, all steps being carried out in a single bed fluid bed coater. 4. The method according to p. A compound according to claim 1, characterized in that the alkaline compound is selected from the group consisting of trisodium phosphate, disodium phosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, aluminum hydroxide, aluminum, calcium, sodium or potassium carbonate, phosphate or citrate, mixed aluminum compounds -magnesium Al ₂ O ₃ · 6 MgO · CO ₂ · 12 H ₂ O or MgO · Al ₂ O ₃ · • 2 SiO ₂ · nH ₂ O and alkaline amino acids. 5. The method according to p. The method of claim 1, wherein the pharmaceutically acceptable excipient is present in an aqueous or hydroalcoholic suspension solution containing a surfactant selected from the group consisting of sodium lauric sulfate, polysorbate, poloxamer or other ionic and nonionic surfactants. 6. The method according to p. The process of claim 1, wherein the pharmaceutically acceptable excipient is present in an aqueous or hydroalcoholic suspension solution containing a filler material selected from the group consisting of lactose, starch, sucrose and microcrystalline cellulose. 7. The method according to p. The process of claim 1, wherein the pharmaceutically acceptable excipient is present in an aqueous or hydroalcoholic suspension solution containing a disintegrating and swelling agent selected from the group consisting of starch, calcium carboxymethyl cellulose, sodium starch glycolate and low-substituted hydroxymethyl cellulose. 8. The method according to p. The method of claim 1, wherein the gastric environment-resistant film-forming polymer is present in the outer coating selected from the group consisting of methyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxybutyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, succinimethyl cellulose, succinimethyl cellulose, succinimethyl cellulose, succinimethyl cellulose. , sodium carboxymethylaminopectin, chitosan, alginic acid, carrageenes, galactomanians, tragacanth, shellac, agar-agar, acacia, guar gum and xanthan gum, poly (acrylic acids), poly (methacrylic acids) and their salts, poly (vinyl alcohol) PVA, polyethylene and propylene oxides and mixtures thereof. 9. The method according to p. The process of claim 1, wherein the pharmaceutically acceptable excipient is present in the outer coating resistant to the stomach environment, containing a plasticizer selected from the group consisting of triethyl citrate, polyethylene glycol, cetyl alcohol and stearyl alcohol. PL 192 961 B1 10. The method according to p. The method of claim 1, wherein the pharmaceutically acceptable excipient is present in the outer coating resistant to the stomach environment, containing a surfactant selected from the group consisting of sodium lauric sulfate, polysorbate and poloxamer. 11. The method according to p. The method of claim 1, wherein the pharmaceutically acceptable excipient is present in the outer coating resistant to the gastric environment, containing a pigment selected from the group consisting of titanium dioxide and iron sesquioxide. 12. The method according to p. The process of claim 1, wherein the pharmaceutically acceptable excipient is present in the outer coating resistant to the stomach environment, containing a lubricant selected from the group consisting of talc, magnesium stearate and glyceryl monostearate. 13. An oral pharmaceutical composition obtained by the method of claim 1. 14. A pharmaceutical composition according to claim 1 The process of claim 13, wherein the inert nucleus is a neutral spherical microgranule which contains two or more substances such as: sorbitol, mannitol, sucrose, starch, microcrystalline cellulose, lactose, glucose, trehalose, maltite or fructose. 15. The pharmaceutical composition of Claim The nucleus of claim 13 or 14, characterized in that it comprises a neutral nucleus having an initial size from 200 to 1800 μπ. preferably from 600 to 900 µπ.